Impact of ABCB1 on neuro-PK of metoclopramide

The blood-brain barrier is the interface between the blood and the brain. It protects the brain from potentially harmful substances, such as chemicals and drugs. This protective function is enhanced by a transporter protein called P-glycoprotein (ABCB1), which can pump many different drugs from the brain into the blood and thereby limit their brain entry. The function of P- glycoprotein can be variable among different people. This can, for instance, be caused by intake of certain drugs, by certain diseases, by age or by genetic factors. Such variability in P- glycoprotein function can determine if drugs which are intended to act in the brain reach the brain in adequate amounts to cure diseases or if they cause side effects in the brain. Positron emission tomography (PET) is an imaging method which can be used to measure P-glycoprotein function in the human brain. For PET examinations, very small amounts of radioactively labelled molecules are administered (so-called PET tracers). Currently available PET tracers are transported with high affinity by P-glycoprotein. They consequently possess a very low uptake in the brain leading to a low sensitivity to measure small changes in P-glycoprotein function in the brain. Many drugs which act in the brain are weak ABCB1 substrates with good permeability through the blood-brain barrier. It is to date not clearly understood how ABCB1 affects the brain distribution of such drugs. We hypothesise that PET tracers based on such drugs will be more sensitive to detect small changes in P-glycoprotein function in the brain than currently available PET tracers. In the present project, we will assess the suitability of a new PET tracer called [11C]metoclopramide, which is a weak P-glycoprotein substrate, to measure P-glycoprotein function in humans. We will perform PET experiments in healthy subjects without and with co- administration of a second drug which inhibits P-glycoprotein. We will also assess the suitability of the new PET tracer to detect a moderate reduction in P-glycoprotein function as it occurs in elderly people. The results of our study will allow us to determine the suitability of the new PET tracer to visualise P-glycoprotein function in humans. Moreover, our study will improve our understanding if ABCB1 contributes to variability in efficacy and side effects of drugs acting in the brain.

The blood-brain barrier is the interface between the blood and the brain. It protects the brain from potentially harmful substances, such as chemicals and drugs. This protective function is enhanced by a transporter protein called P-glycoprotein (P-gp), which can pump many different drugs from the brain into the blood and thereby limit their brain entry. The activity of P-gp can be variable among different people. This can, for instance, be caused by intake of certain drugs, by certain diseases, by age or by genetic factors. Such variability in P-gp activity can determine if drugs which are intended to act in the brain reach the brain in adequate amounts to cure diseases or if they cause side effects in the brain. Positron emission tomography (PET) is an imaging method which can be used to measure P-gp activity in the human brain. For PET examinations, very small amounts of radioactively labeled molecules are administered (so-called PET tracers). Currently available PET tracers are transported with high affinity by P-gp. They consequently possess a very low uptake in the brain leading to a low sensitivity to measure small changes in P-gp activity in the brain. Many drugs which act in the brain are weak P-gp substrates with good permeability through the blood-brain barrier. It is to date not clearly understood how P-gp affects the brain distribution of such drugs. We hypothesize that PET tracers based on such drugs will be more sensitive to detect small changes in P-gp activity in the brain than currently available PET tracers. In the present project, we assessed the suitability of a new PET tracer called [11C]metoclopramide, which is a weak P-gp substrate, to measure P-gp activity in humans. We performed PET experiments in healthy persons without and with co-administration of a second drug which inhibits P-gp. We also assessed the suitability of the new PET tracer to detect a moderate reduction in P-gp activity as it occurs in elderly people. We could show that [11C]metoclopramide is transported by P-gp at the human blood-brain barrier and that it possesses sufficient sensitivity to detect an age-related reduction in P-gp activity in the brain. The obtained results pave the way for a future use of [11C]metoclopramide as a PET tracer for P-gp in humans.